The inflammation hypothesis of aging centers on the assertion that aging is the accumulation of damage, which results from chronic activity of immune response systems. Overproduction of pro-inflammatory cytokines has been linked to a number of chronic conditions common in older adults including cardiovascular disease, frailty, cognitive decline, dementia, and overall mortality. Evidence that pro-inflammatory cytokines contribute to fracture, however, does not exist despite animal and in-vitro data supporting such an association. Fractures are the most devastating consequence of osteoporosis. Preliminary analyses from the Health, Aging and Body Composition (Health ABC) study suggest that higher soluble cytokine receptor levels are associated with faster rates of bone loss and an increased risk of fracture. However, Health ABC data are based on only 40 fractures in older men and there is no systematic assessment of incident vertebral fracture, the most common osteoporotic fracture. The Osteoporotic Fractures in Men (MrOS) study is the first comprehensive study of aging men's skeletal health in the U.S. Osteoporosis is an important public health problem since about 30% of men over age 60 will experience a fracture. The current proposal will expand on these preliminary data and focus on the relationship of pro-inflammatory cytokines and vertebral and nonspine fracture in older men. In addition, we will measure osteoprotegrin, an anti-inflammatory cytokine that plays a key role in osteoclastgenesis. The mechanisms that may underlie these complex processes where inflammation may lead to fractures are unknown. A major question is whether there is a direct effect of inflammatory cytokines on bone loss and fracture, or is this a function of reduced sex steroid hormones levels leading to unrestrained cytokine production and increased bone turnover and fracture. Likewise, we will address whether the association is affected by modifiable factors such as regular physical activity and abdominal adiposity, which appear to be involved in the regulation and production of inflammatory cytokines. The proposed study is uniquely positioned to address these questions in a novel yet systematic approach for defining the connection between cytokines and fracture risk. Using data, CT scans and stored specimens from MrOS, levels of pro-inflammatory cytokine soluble receptors (TNFa-sRI and sRII, IL-6SR and the antiinflammatory cytokine, OPG, will be compared between men who experienced incident non-spine and vertebral fracture and a random sample (2:1 ratio) of men who did not experience fracture as of July 2006. We will use information on sex steroid hormones and bone turnover in the same cases and controls which is available from other ancillary grants. In addition, we will examine the influence of physical activity and abdominal adipose tissue distribution on cytokine levels and fracture risk. Understanding the biological mechanisms for these associations could lead to the development and testing of preventive interventions.